Abstract There are very few systematic studies on humans that focus on changing the underlying traumatic memory once PTSD has been established. The proposed project is a translational study based on our work with animal models of PTSD in which coricosterone augmented extinction of contextual fear memories. The study design is a double-blind randomized controlled clinical trial involving eighty-eight OEF/OIF veterans with combat-related PTSD. We plan to pair multiple fear memory reactivations, using a scripted imagery technique, with an oral glucocorticoid or placebo. Participants will be followed at 1, 3, and 6 months post intervention to measure the longevity of the expected effect. Outcome measures will include PTSD symptom severity, depression symptoms severity, and physiological measures. Specific Aims/Hypothesis: Aim 1: Examine the effects of glucocorticoid administration following traumatic memory reactivation on psychiatric symptoms in veterans with combat-related PTSD. Specific hypotheses to be tested: (A) Subjects who receive an exogenous glucocorticoid after traumatic memory reactivation will demonstrate fewer PTSD and depression symptoms one week later, compared to those who receive a placebo after traumatic memory reactivation. (B) The glucocorticoid reduction effects will be cumulative; that is, reduction will persist, and further post- reactivation glucocorticoid administration will further reduce symptoms. (C) Decreases in PTSD and depression symptoms will persist at 1, 3, and 6 months for subjects receiving an exogenous glucocorticoid compared to those subjects receiving placebo. Aim 2: Examine the effects of glucocorticoid administration following traumatic memory reactivation on physiological responses to veteran's personal combat memories. (D) Subjects who receive an exogenous glucocorticoid after traumatic memory reactivation will demonstrate decreased physiological responses one week later, compared to those who receive a placebo after traumatic memory reactivation. (E) As with the psychological measures, suppression of the physiological measures will demonstrate both persistence over time and accumulation with subsequent post-reactivation glucocorticoid administration.